Inhibitors of serine proteases

Abstract

This invention relates to compounds of formula I: or a pharmaceutically acceptable salt or mixtures thereof wherein C* represents a diastereomeric carbon comprising a mixture of R and S isomers wherein the R isomer is greate than 50% of the mixture.

1 . A mixture of diastereomeric compounds of Formula I:  
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt or mixtures thereof, wherein 
 C* represents a diasteromeric carbon atom; and  
 the R isomer is greater than 50% of the mixture relative to the S isomer at the C* position;  
 R 1  is RW—, P 3 —, or P 4 -L 2 -P 3 —;  
 R is an optionally substituted aliphatic, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl;  
 W is a bond, —NR4—, —O—, or —S—;  
 R 4  is H, an optionally substituted aliphatic, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl;  
 P 3 — is  
                     
 T is —C(O)—, —OC(O)—, —NHC(O)—, —C(O)C(O)—, or —SO 2 —;  
 Each of R 5  and R 5 ′ is independently H, an optionally substituted aliphatic, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted phenyl, or an optionally substituted heteroaryl;  
 R 6  is an optionally substituted aliphatic, an optionally substituted heteroaryl, an optionally substituted phenyl; or R 5  and R 6 , together with the atoms to which they are attached, may form a 5- to 7-membered optionally substituted monocyclic heterocycloaliphatic, or a 6- to 12-membered optionally substituted bicyclic heterocycloaliphatic, in which each heterocycloaliphatic ring optionally contains an additional heteroatom selected from —O—, —S— or —NR 50 —;  
 R 50  is H, an optionally substituted aliphatic, an optionally substituted heteroaryl, or an optionally substituted phenyl;  
 P 4 -L 2 -P 3  is  
                     
 Each of R 7  and R 7 ′ is independently H, an optionally substituted aliphatic, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted phenyl, or an optionally substituted heteroaryl; or  
 R 7  and R 7 ′, together with the atom to which they are attached, may form a 3- to 7-membered cycloaliphatic or heterocycloaliphatic ring; or  
 R 7  and R 6 , together with the atoms to which they are attached, may form a 5- to 7-membered optionally substituted monocyclic heterocycloaliphatic, a 5- to 7-membered optionally substituted monocyclic heteroaryl, a 6- to 12-membered optionally substituted bicyclic heterocycloaliphatic, or a 6- to 12-membered optionally substituted bicyclic heteroaryl, in which each heterocycloaliphatic or heteroaryl ring optionally contains an additional heteroatom selected from —O—, —S— or —NR 50 —, or  
 When R 5  and R6, together with the atoms to which they are attached, may form a ring; R 7  and the ring system formed by R 5  and R 6  may form an 8- to 14-membered optionally substituted bicyclic fused ring system, wherein the bicyclic fused ring system is optionally further fused with an optionally substituted phenyl to form an optionally substituted 10- to 16-membered tricyclic fused ring system;  
 R 8  is H or a protecting group; and  
 R 2  is an optionally substituted aliphatic, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted heteroaryl, or an optionally substituted phenyl;  
 R 3  is H, an optionally substituted aliphatic, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl;  
 L is a bond, —CF 2 —, —C(O)—, or —SO 2 —;  
 Each of J 1 , J 2 , J′ 2 , and J 3  is independently halogen, —OR′, —OC(O)N(R′) 2 , —NO 2 , —CN, —CF 3 , —OCF 3 , —R′, oxo, thioxo, —N(R′) 2 , —SR′, —COR′, —SO 2 R′, —SO 2 N(R′) 2 , —SO 3 R′, —C(O)R′, —C(O)C(O)R′, —C(O)CH 2 C(O)R′, —C(S)R′, —C(O)OR′, —OC(O)R′, —C(O)N(R′) 2 , —OC(O)N(R′) 2 , —C(S)N(R′) 2 , —(CH 2 ) 0-2 NHC(O)R′, —N(R′)N(R′)COR′, —N(R′)N(R′)C(O)OR′, —N(R′)N(R′)CON(R′) 2 , —N(R′)SO 2 R′, —N(R′)SO 2 N(R′) 2 , —N(R′)C(O)OR′, —N(R′)C(O)R′, —N(R′)C(S)R′, —N(R′)C(O)N(R′) 2 , —N(R′)C(S)N(R′) 2 , —N(COR′)COR′, —N(OR′)R′, —C(═NH)N(R′) 2 , —C(O)N(OR′)R′, —C(═NOR′)R′, —OP(O)(OR′) 2 , —P(O)(R′) 2 , —P(O)(OR′) 2 , or —P(O)(H)(OR′), or of J 2  and J′ 2  is H, wherein;  
 Two R′ groups together with the atoms to which they are bound may form a 3- to 10-membered aromatic or non-aromatic ring system having up to 3 heteroatoms independently selected from N, O, or S, wherein the ring is optionally fused to a C 6 -C 10  aryl, a C 5 -C 10  heteroaryl, a C 3 -C 10  cycloalkyl, or a C 3 -C 10  heterocycloaliphatic, and wherein any ring has up to 3 substituents each independently selected from J 2 ;  
 Each R′ is independently selected from H, C 1 -C 12  aliphatic, C 3 -C 10  cycloalkyl, or C 3 -C 10  cycloalkenyl, C 3 -C 10  cycloalkyl-C 1 -C 12  aliphatic, C 3 -C 10  cycloalkenyl-C 1 -C 12  aliphatic, C 6 -C 10  aryl, C 6 -C 10  aryl-C 1 -C 12  aliphatic, 3- to 10-membered heterocycloaliphatic, 6- to 10-membered heterocycloaliphatic-C 1 -C 12  aliphatic, 5- to 10-membered heteroaryl, or 5- to 10-membered heteroaryl-C 1 -C 12  aliphatic, wherein R′ has up to 3 substituents each independently selected from J 2 ; or  
 J 1  and J 2 , together with the atoms to which they are attached, may form a C 8  to C 12  optionally substituted bicyclic ring;  
 J 1  and J 3 , together with the atoms to which they are attached, may form a C 8  to C 12  optionally substituted bicyclic ring;  
 J 2  and J′ 2 , together with the carbon atom to which they are attached, may form an optionally substituted 5-10 membered cycloaliphatic, or an optionally substituted 5- to 10-membered heterocycloaliphatic ring; or  
 J 2  and J 3 , together with the atoms to which they are attached, may form a C 8  to C 12  optionally substituted bicyclic ring.  
 
   
   
       2 . The mixture of diastereomeric compounds according to  claim 1 , wherein the  
     
       
         
         
             
             
         
       
     
     molety is  
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     wherein n is 0 or 1 and each of Z and Z′ is independently —CR′R′—, S, or O.  
   
   
       3 . The mixture of diastereomeric compounds according to  claim 1 , wherein J 1  and J 2 , together with the atoms to which they are attached, form an optionally substituted mono- or bicyclic ring such that the  
     
       
         
         
             
             
         
       
     
     moiety is  
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       4 . The mixture of diastereomeric compounds according to  claim 1 , wherein J 2  and J 3 , together with the atoms to which they are attached, form an optionally substituted mono- or bicyclic ring such that the  
     
       
         
         
             
             
         
       
     
     moiety is  
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       5 . The mixture of diastereomeric compounds according to  claim 1 , wherein when J 1  and J 3 , together with the atoms to which they are attached, form an optionally substituted monocyclic aliphatic ring such that the  
     
       
         
         
             
             
         
       
     
     moiety is  
     
       
         
         
             
             
         
       
     
   
   
       6 . The mixture of diastereomeric compounds according to  claim 1 , wherein J 1  and J 2  together with the atoms to which they are attached form a monocyclic ring such that the  
     
       
         
         
             
             
         
       
     
     moiety is  
     
       
         
         
             
             
         
       
     
   
   
       7 . The mixture of diastereomeric compounds of  claim 6 , wherein L is —C(O)—.  
   
   
       8 . The mixture of diastereomeric compounds according to  claim 7 , wherein R 1  is  
     
       
         
         
             
             
         
       
     
   
   
       9 . The mixture of diastereomeric compounds according to  claim 1 , wherein R 1  is RW—.  
   
   
       10 . The mixture of diastereomeric compounds according to  claim 9 , wherein R is an optionally substituted aliphatic, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl; and W is a bond, —O—, —S—, or —NR 4 —.  
   
   
       11 . The mixture of diastereomeric compounds according to  claim 10 , wherein R is an optionally substituted aryl or an optionally substituted heteroaryl; and W is —O—.  
   
   
       12 . The mixture of diastereomeric compounds according to  claim 10 , wherein R is an optionally substituted aliphatic or an optionally substituted cycloaliphatic.  
   
   
       13 . The mixture of diastereomeric compounds according to  claim 12 , wherein R is an optionally substituted arylalkyl or an optionally substituted heteroarylalkyl.  
   
   
       14 . The mixture of diastereomeric compounds according to  claim 10 , wherein RW— is  
     
       
         
         
             
             
         
       
     
   
   
       15 . The mixture of diastereomeric compounds according to  claim 6 , wherein R 1  is P 3 , P 3  is  
     
       
         
         
             
             
         
       
     
     and 
 Each of R 5  and R′ 5  is independently an optionally substituted aliphatic, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl;  
 R 6  is an optionally substituted aliphatic, an optionally substituted cycloaliphatic, an optionally substituted heteroaryl, an optionally substituted phenyl; or  
 R 5  and R 6 , together with the atoms to which they are attached, form a 5- to 7-membered optionally substituted monocyclic heterocycle, or a 6- to 12-membered optionally substituted bicyclic heterocycle, in which each heterocycle ring optionally contains an additional heteroatom selected from —O—, —S— or —NR 50 —; and  
 T is —C(O)—, —OC(O)—, —NHC(O)—, —C(O)C(O)—, or —SO 2 —.  
 
   
   
       16 . The mixture of diastereomeric compounds according to  claim 15 , wherein T is —C(O)—.  
   
   
       17 . The mixture of diastereomeric compounds according to  claim 15 , wherein T is —OC(O)—.  
   
   
       18 . The mixture of diastereomeric compounds according to  claim 15 , wherein T is —NHC(O)—.  
   
   
       19 . The mixture of diastereomeric compounds according to  claim 15 , wherein T is —C(O)C(O)—.  
   
   
       20 . The mixture of diastereomeric compounds according to  claim 15 , wherein T is —S(O) 2 —.  
   
   
       21 . The mixture of diastereomeric compounds according to  claim 6 , wherein R 1  is P 4 -L 2 -P 3 —; and P 4 -L 2 -P 3 — is  
     
       
         
         
             
             
         
       
     
     wherein 
 Each of R 7  and R 7 ′ is independently H, an optionally substituted aliphatic, an optionally substituted heteroaryl, or an optionally substituted phenyl; or R 7  and R 7 ′, together with the atom to which they are attached, may form a 3- to 7-membered cycloaliphatic or heterocycloaliphatic ring; or R 7  and R 6 , together with the atoms to which they are attached, may form a 5- to 7-membered optionally substituted monocyclic heterocycloaliphatic, a 5- to 7-membered optionally substituted monocyclic heteroaryl, a 6- to 12-membered optionally substituted bicyclic heterocycloaliphatic, or a 6- to 12-membered optionally substituted bicyclic heteroaryl, in which each heterocycloaliphatic or heteroaryl ring optionally contains an additional heteroatom selected from —O—, —S— or —NR 50 —; or  
 When R 5  and R 6 , together with the atoms to which they are attached, form a ring, R 7  and the ring system formed by R 5  and R 6  may form an 8- to 14-membered optionally substituted bicyclic fused ring system, wherein the bicyclic fused ring system is optionally further fused with an optionally substituted phenyl to form an optionally substituted 10- to 16-membered tricyclic fused ring system;  
 R 8  is H or a protecting group.  
 R 50  is H, an optionally substituted aliphatic, an optionally substituted heteroarvl, or an optionally substituted phenyl.  
 
   
   
       22 . The mixture of diastereomeric compounds according to  claim 21 . wherein R 7 ′ is H; and R 7  is C 1 -C 6  alkyl, C 3 -C 10  cycloalkyl, C 3 -C 10  cycloalkyl-C 1 -C 12  alkyl, C 6 -C 10  aryl, C 6 -C 10  aryl-C 1 -C 6  alkyl, 3-to 10-membered heterocycloaliphatic, 6- to 10-membered heterocycloaliphatic-C 1 -C 12  alkyl, 5- to 10-membered heteroaryl, or 5- to 10-membered heteroaryl-C 1 -C 12  alkyl.  
   
   
       23 . The mixture of diastereomeric compounds of  claim 22 , wherein R 7  is  
     
       
         
         
             
             
         
       
     
   
   
       24 . The mixture of diastereomeric compounds of  claim 21 , wherein R 7  and R 7 ′, together with the atom to which they are attached, form a 3- to 7-membered optionally substituted cycloaliphatic ring.  
   
   
       25 . The mixture of diastereomeric compounds of  claim 24 , wherein R 7  and R 7 ′, together with the atom to which they are attached, form  
     
       
         
         
             
             
         
       
     
   
   
       26 . The mixture of diastereomeric compounds of  claim 22 , wherein R is  
     
       
         
         
             
             
         
       
     
   
   
       27 . The mixture of diastereomeric compounds of  claim 22 , wherein R is  
     
       
         
         
             
             
         
       
     
   
   
       28 . The mixture of diastereomeric compounds of  claim 22 , wherein R is:  
     
       
         
         
             
             
         
       
       Wherein R 10  is H, C 1 - 12  aliphatic, C 6 - 10  aryl, C 6 - 10  aryl-CI- 12  aliphatic, C 3 - 10  cycloalkyl, C 3 - 10  cycloalkenyl, C 3 - 10  cycloalkyl-C 1 - 12  aliphatic, C 3 - 10  cycloalkenyl-C 1 - 12  aliphatic, 3- to 10-membered heterocycloaliphatic, 6- to 10-membered heterocycloaliphatic-C 1 - 12  aliphatic, 5- to 10-membered heteroaryl, or 5- to 10-membered heteroaryl-C 1 - 12  aliphatic;  
       K is a bond, C 1 - 12  aliphatic, —O—, —S—, —NR 9 —, —C(O)—, or —C(O)NR 9 —, wherein R 9  is H or C 1 - 12  aliphatic; and  
       m is 1,2, or 3.  
     
   
   
       29 . The mixture of diastereomeric compounds of  claim 22 , wherein R is  
     
       
         
         
             
             
         
       
     
   
   
       30 . The mixture of diastereomeric compounds of  claim 22 , wherein R is  
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     wherein 
 Z 2 is O, S, NR 10 , or C(R 10 ) 2 ;  
 Each R 10  is independently H, C 1 - 12  aliphatic, C 6 -10 aryl, C 6 - 10  aryl-C 1 - 12  aliphatic, C 3 - 10 cycloalkyl, C 3 - 10  cycloalkenyl, C 3 - 1 O cycloalkyl-CI-12 aliphatic, C 3 - 10  cycloalkenyl-aliphatic, 3- to 10-membered heterocycloaliphatic, 6- to 10-membered heterocycloaliphatic-C 1 - 12  aliphatic, 5- to 10-membered heteroaryl, or 5- to 10-membered heteroaryl-C 1 - 12  aliphatic;  
 p is 1 or 2; and  
    is a single bond or a double bond.  
 
   
   
       31 . The mixture of diastereomeric compounds according to  claim 21 , wherein T is a bond; and R is an optionally substituted (heterocycloaliphatic)aliphatic.  
   
   
       32 . The mixture of diastereomeric compounds according to  claim 21 , wherein T is a bond; and R is an optionally substituted aryl or an optionally substituted heteroaryl.  
   
   
       33 . The mixture of diastereomeric compounds according to  claim 21 , wherein T is —C(O)—; and R is —NR 4 .  
   
   
       34 . The mixture of diastereomeric compounds according to  claim 1 , wherein R 2  is an optionally substituted aliphatic, an optionally substituted phenyl, an optionally substituted cycloaliphatic, or an optionally substituted heterocycloaliphatic.  
   
   
       35 . The mixture of diastereomeric compounds of  claim 34 , wherein R 2  is  
     
       
         
         
             
             
         
       
     
   
   
       36 . The mixture of diastereomeric compounds according to  claim 34 , wherein R 2  is n-propyl.  
   
   
       37 . The mixture of diastereomeric compounds according to  claim 1 , wherein R 3  is an optionally substituted C 1 -C 7  aliphatic, an optionally substituted cycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl.  
   
   
       38 . The mixture of diastereomeric compounds according to  claim 37 , wherein R 3  is an optionally substituted C 1 -C 6  alkyl or an optionally substituted C 1 -C 6  cycloalkyl.  
   
   
       39 . The mixture of diastereomeric compounds according to  claim 38 , wherein R 3  is  
     
       
         
         
             
             
         
       
     
   
   
       40 . The mixture of diastereomeric compounds according to  claim 39 , wherein R 3  is cyclopropyl.  
   
   
       41 . A mixture of diastereomeric compounds, comprising:  
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt or mixtures thereof, wherein C* represents a mixture of the R and S isomers; and the R isomer is greater than 50% of the mixture relative to the S isomer at the C* position.  
   
   
       42 . The mixture of diastereomeric compounds according to  claim 41 , wherein the percentage of the R isomer in the mixture is greater than 60%.  
   
   
       43 . The mixture of diastereomeric compounds according to  claim 42 , wherein the percentage of the R isomer in the mixture is greater than 70%.  
   
   
       44 . The mixture of diastereomeric compounds according to  claim 43 , wherein the percentage of the R isomer in the mixture is greater than 80%.  
   
   
       45 . The mixture of diastereomeric compounds according to  claim 44 , wherein the percentage of the R isomer in the mixture is greater than 90%.  
   
   
       46 . The mixture of diastereomeric compounds according to  claim 45 , wherein the percentage of the R isomer in the mixture is greater than 95%.  
   
   
       47 . The mixture of diastereomeric compounds according to  claim 46 , wherein the percentage of the R isomer in the mixture is greater than 98%.  
   
   
       48 . The mixture of diastereomeric compounds according to  claim 47 , wherein the percentage of the R isomer in the mixture is greater than 99%.  
   
   
       49 . A pharmaceutical composition comprising a mixture of diastereomeric compounds according to  claim 1 , in an amount effective to inhibit a serine protease; and an acceptable carrier, adjuvant or vehicle.  
   
   
       50 . A pharmaceutical composition comprising a mixture of diastereomeric compounds according to  claim 41 , in an amount effective to inhibit a serine protease; and an acceptable carrier, adjuvant or vehicle.  
   
   
       51 . The composition according to  claim 50 , wherein said composition is formulated for administration to a patient.  
   
   
       52 . The composition according to  claim 50 , further comprising an immunomodulatory agent, an antiviral agent, a second inhibitor of HCV protease, an inhibitor of another target in the HCV life cycle, and a cytochrome P-450 inhibitor, or any combination thereof.  
   
   
       53 . The composition according to  claim 51 , wherein said immunomodulatory agent is α-, β-, or γ-interferon or thymosin; said antiviral agent is ribavirin, amantadine, or telbivudine; or said inhibitor of another target in the HCV life cycle is an inhibitor of HCV helicase, polymerase, or metalloprotease.  
   
   
       54 . The composition according to  claim 52 , wherein said cytochrome P-450 inhibitor is ritonavir.  
   
   
       55 . A method of inhibiting the activity of a serine protease comprising the step of contacting said serine protease with a mixture of diastereomeric compounds according to  claim 1 , or a composition according to  claim 49 , in a pharmaceutically effective amount.  
   
   
       56 . A method of inhibiting the activity of a serine protease comprising the step of contacting said serine protease with a mixture of diastereomeric compounds according to  claim 41 , or a composition according to  claim 50 , in a pharmaceutically effective amount.  
   
   
       57 . The method according to  claim 56 , wherein said serine protease is an HCV NS3 protease.  
   
   
       58 . A method of treating an HCV infection in a patient comprising the step of administering to said patient a mixture of diastereomeric compounds according to  claim 1 , or a composition according to  claim 49 , in a pharmaceutically effective amount.  
   
   
       59 . A method of treating an HCV infection in a patient comprising the step of administering to said patient a mixture of diastereomeric compounds according to  claim 41 , or a composition according to  claim 50 , in a pharmaceutically effective amount.  
   
   
       60 . The method according to  claim 59 , further comprising the additional step of administering to said patient an additional agent selected from an immunomodulatory agent; an antiviral agent; a second inhibitor of HCV protease; an inhibitor of another target in the HCV life cycle; or combinations thereof; wherein said additional agent is administered to said patient as part of said composition according to  claim 49  or as a separate dosage form.  
   
   
       61 . The method according to  claim 60 , wherein said immunomodulatory agent is α-, β-, or γ-interferon or thymosin; said antiviral agent is ribavarin or amantadine; or said inhibitor of another target in the HCV life cycle is an inhibitor of HCV helicase, polymerase, or metalloprotease.  
   
   
       62 . A method of eliminating or reducing HCV contamination of a biological sample or medical or laboratory equipment, comprising the step of contacting said biological sample or medical or laboratory equipment with a mixture of diastereomeric compounds according to  claim 1 , or a composition according to  claim 49 .  
   
   
       63 . A method of eliminating or reducing HCV contamination of a biological sample or medical or laboratory equipment, comprising the step of contacting said biological sample or medical or laboratory equipment with a mixture of diastereomeric compounds according to  claim 41 , or a composition according to  claim 50 .  
   
   
       64 . The method according to  claim 63 , wherein said sample or equipment is selected from blood, other body fluids, biological tissue, a surgical instrument, a surgical garment, a laboratory instrument, a laboratory garment, a blood or other body fluid collection apparatus; a blood or other body fluid storage material.  
   
   
       65 . The method according to  claim 64 , wherein said body fluid is blood.  
   
   
       66 . The compound (1S,3aR,6aS)-2-[(2S)-2-[[(2S)-2-cyclohexyl-1-oxo-2-[(pyrazinylcarbonyl)amino]ethyl]amino]-3,3-dimethyl-1-oxobutyl]-N-[(1R)-1-[2-(cyclopropylamino)-1,2-dioxoethyl]butyl]octahydro-cyclopenta[c]pyrrole-1-carboxamide.  
   
   
       67 . A pharmaceutical composition comprising the compound according to  claim 66 , in an amount effective to inhibit a serine protease; and a acceptable carrier, adjuvant or vehicle.  
   
   
       68 . A method of inhibiting the activity of a serine protease comprising the step of contacting said serine protease with the compound according to  claim 66  or the composition according to  claim 67.